Gene Therapies Fail To Slow 2 Deadly Diseases

Results Disappoint In Cystic Fibrosis, Duchenne Studies

September 28, 1995|By Peter Gorner, Tribune Staff Writer.

Two of the largest and most carefully controlled studies ever done of gene therapy for two lethal inherited diseases-cystic fibrosis and Duchenne muscular dystrophy-indicate that when healthy genes were delivered into patients' bodies, the genes didn't help them.

However, gene therapists are likely to classify as old news the studies published in Thursday's New England Journal of Medicine. As a proponent wrote in an accompanying editorial, early failures are understandable in a field only five years old where current tools are "quite crude."

Duchenne is the most common and severe form of muscular dystrophy, a group of inherited disorders in which the muscles of the body progressively degenerate. Mostly young boys are affected by Duchenne-about 30,000 in the U.S.-and few survive to adulthood.

Cystic fibrosis, the most common fatal genetic disease among white people, results in excessively thick mucus secretions in the lungs that trap disease-causing bacteria, causing debilitating infections that eventually destroy the lungs.

When the gene responsible for Duchenne was discovered in 1986, scientists quickly were able to identify the protein, which they named dystrophin, that is missing in Duchenne victims. But how to deliver a healthy version of the dystrophin-making gene to the body's huge muscle masses has stymied researchers.

Since 1990, U.S. and Canadian physicians have tried to place the gene in boys with Duchenne via transplants of immature muscle cells called myoblasts. Only one scientist, Dr. Peter Law, a controversial Memphis neurologist, claimed success.

Although myoblasts are under intense study as gene-delivery vehicles to different parts of the body, they don't work in Duchenne muscular dystrophy, according to the newest study.

Ohio State University neurologist Jerry Mendell, a veteran Duchenne researcher, showed little or no persistence of injected myoblasts in 11 of 12 boys treated, and no improvement in the strength of the muscle that received the injection in any patient over the six months of the trial.

Cystic fibrosis affects an estimated 35,000 people in the U.S. and Canada. Although life expectancies have lengthened in recent years due to better care, most patients still die by their early 30s. Each year the disease claims the lives of some 1,500 people.

So far, delivery of the gene to heal cystic fibrosis, a gene discovered in 1989 after a half-century search, has relied on aerosol concoctions to the nose, the windpipe, and in a handful of cases, to the lungs themselves.

Studies have shown that correcting only 6 percent of the proper cells could cure CF, which is considered a genetic model for the common lung diseases emphysema and chronic bronchitis.

The latest cystic fibrosis trial transferred genes to the nasal passages using genetically engineered viruses, called adenoviruses, that cause the common cold. Nose tissue, the scientists speculated, was similar enough to lung tissue that some improvement should have been noted.

Physicians at the University of North Carolina at Chapel Hill School of Medicine tested the therapy on 12 young adult volunteers with mild to moderate cystic fibrosis. They found the adenovirus "vector," or shuttle, for the healthy genes did not correct the cystic fibrosis defect.

"Several solutions appear possible," said Dr. Richard Boucher, who directs the university's Cystic Fibrosis Research Center. "Either the adenovirus carrier must be re-engineered so it can target affected cells, or new ways developed to make the cells more receptive to the adenovirus, or new shuttle vectors selected that will efficiently target those cells."

However, many researchers have rejected nose tissue as a model-another model places genes directly into the bloodstream via pulmonary circulation-and have moved swiftly past the vectors used in the trials to more sophisticated versions.

"We are confident that gene therapy will someday provide a cure for CF," said Dr. Claude Lenfant, director of the National Heart, Lung, and Blood Institute. "Significant advances hinge on this crucial interplay between `bench' and bedside research."

Even in its infancy, gene therapy has exploded into more than 100 clinical trials involving patients with a host of deadly illnesses, ranging from AIDS and cancer to atherosclerosis.

In addition to the airways, adenovirus vectors have been shown to shuttle genes to liver, blood vessels, brain, muscle, heart, peritoneum, salivary glands, and to tumor cells as a possible treatment for lung cancer.